Compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response

ABSTRACT

The present invention provides a compound that is represented by the following general formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , X, W, X and Y are as defined in the specification. The compounds may be administered to treat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases or conditions.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61,580,474, filed Dec. 27, 2011, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds, to processes for their preparation,to pharmaceutical compositions containing them and to their use inmedicine, in particular their use in the treatment of conditionsmediated by the action of ligands for the DP₁, FP, TP, EP₁ and EP₄prostaglandin (PG) receptors. The present compounds have the generalstructure shown below and act at different prostaglandin receptors tothereby provide a general anti-inflammatory response.

2. Summary of the Related Art

The EP₁ receptor is a 7-transmembrane receptor and its natural ligand isthe prostaglandin PGE₂. PGE₂ also has affinity for the other EPreceptors (types EP₂, EP₃ and EP₄). The EP₁ receptor is associated withsmooth muscle contraction, pain (in particular inflammatory, neuropathicand visceral), inflammation, allergic activities, renal regulation andgastric or enteric mucus secretion.

Prostaglandin E₂ (PGE₂) exerts allodynia through the EP₁ receptorsubtype and hyperalgesia through EP₂ and EP₃ receptors in the mousespinal cord. Furthermore, it has been shown that in the EP₁ knock-outmouse pain-sensitivity responses are reduced by approximately 50%. EP₁receptor antagonist (ONO-8711) reduces hyperalgesia and allodynia in arat model of chronic constriction injury and inhibits mechanicalhyperalgesia in a rodent model of post-operative pain. The efficacy ofEP₁ receptor antagonists in the treatment of visceral pain in a humanmodel of hypersensitivity has been demonstrated. Thus, selectiveprostaglandin ligands, agonists or antagonists, depending on whichprostaglandin E receptor subtype is being considered, haveanti-inflammatory, antipyretic and analgesic properties similar to aconventional non-steroidal anti-inflammatory drug, and in addition,inhibit hormone-induced uterine contractions and have anti-cancereffects. These compounds have a diminished ability to induce some of themechanism-based side effects of NSAIDs which are indiscriminatecyclooxygenase inhibitors. In particular, the compounds have a reducedpotential for gastrointestinal toxicity, a reduced potential for renalside effects, a reduced effect on bleeding times and a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.Moreover, as a result of sparing potentially beneficial prostaglandinpathways, these agents may have enhanced efficacy over NSAIDS and/orCOX-2 inhibitors. (See Pub. No. US 2005/0065200, which is herebyincorporated by reference, for other diseases that may be treated by EP4receptor antagonists.)

The TP (also known as TxA₂) receptor is a prostanoid receptor subtypestimulated by the endogenous mediator thromboxane. Activation of thisreceptor results in various physiological actions primarily incurred byits platelet aggregatory and smooth muscle constricting effects, thusopposing those of prostacyclin receptor activation.

TP receptors have been identified in human kidneys in the glomerulus andextraglomerular vascular tissue. Activation of TP receptors constrictsglomerular capillaries and suppresses glomerular filtration ratesindicating that TP receptor antagonists could be useful for renaldysfunction in glomerulonephritis, diabetes mellitus and sepsis.

Activation of TP receptors induces bronchoconstriction, an increase inmicrovascular permeability, formation of mucosal edema and mucussecretion, which are typical characteristic features of bronchialasthma. TP antagonists have been investigated as potential asthmatreatments resulting in, for example, orally active Seratrodast(AA-2414). Ramatroban is another TP receptor antagonist currentlyundergoing phase III clinical trials as an anti-asthmatic compound.

Since the DP₁ receptor may trigger an asthmatic response in certainindividuals, compounds that have DP₁ antagonist properties may be usefulas anti-asthmatic drugs. (See Pub. No. 2004/0162323 for the disclosureof other diseases and conditions that may be treated with DPantagonists.)

Finally, the FP receptor modulates intraocular pressure and mediatessmooth muscle contraction of the sphincter muscles in thegastrointestinal tract and the uterus. Thus, antagonists of the FPreceptor are useful for treating reproductive disorders. (See U.S. Pat.No. 6,511,999 for other diseases and conditions that may be treated withFP receptor antagonists.)

As further background for the present invention, see US Published PatentApplication 2007/0060596 which is hereby incorporated by reference inits entirety.

BRIEF SUMMARY OF THE INVENTION

This invention provides a compound, that is a 1-[(5-halo or alkyl orfluoroalkyl or alkoxy-2-{(hydrocarbyl or substitutedhydrocarbyl)oxy}phenyl)methyl]-(3 and/or 5-alkyl orfluoroalkyl)-1H-pyrazole-4-(carboxylic acid or methylene carboxylicacid) or an alkyl or aryl ester or sulfonamide thereof.

In the compound of this invention said halo may be selected from thegroup consisting of chloro and bromo and said hydrocarbyl may beselected from the group consisting of alkyl and carbocyclic aryl.

Preferably, said hydrocarbyl is selected from the group consisting ofbranched chain alkyl and phenyl and more preferably said hydrocarbyl isselected from the group consisting of branched chain alkyl having from 4to 7 carbons.

The compound of this invention may be a 1-[(5-chloro or bromo-ortrifluoromethyl-2-{hydrocarbyloxy}phenyl)methyl]-(3 and/or-5 methyl)-1H-pyrazole-4-carboxylic acid, wherein said hydrocarbyl is selected fromthe group consisting of alkyl and carbocyclic aryl and wherein saidhydrocarbyl may be selected from the group consisting of branched chainalkyl and phenyl, e.g. a branched chain alkyl having from 4 to 7carbons.

Most preferably, the compound of this invention is selected from thegroup consisting of:

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-methylenecarboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-1H-pyrazole-4-carboxylicacid;

1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3-propyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-propyl-1H-pyrazole-4-carboxylicacid;

1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid; and,

1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid.

More preferably, the compound of this invention is selected from thegroup consisting of:

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-methylenecarboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-1H-pyrazole-4-carboxylicacid;

1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-propyl-1H-pyrazole-4-carboxylicacid;

1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-(5-chloro-2-isobutoxy-benzyl)-5-methyl-1h-pyrazole-4-carboxylic acid;

1-(5-chloro-2-cyclopentylmethoxy-benzyl)-5-methyl-1h-pyrazole-4-carboxylicacid;

1-(5-bromo-2-isobutoxy-benzyl)-5-methyl-1h-pyrazole-4-carboxylic acid;

1-[5-bromo-2-(2,2-dimethyl-propoxy)-benzyl]-5-methyl-1h-pyrazole-4-carboxylicacid;

1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-5-methyl-1h-pyrazole-4-carboxylicacid; and,

5-amino-1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazole-4-carboxylicacid.

Most preferably, said compound is:

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-methylenecarboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid; or,

5-amino-1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazole-4-carboxylicacid.

The invention further relates to pharmaceutical compositions containingthe above compounds in combination with a pharmaceutically-acceptableexcipient and to their use in medicine, in particular their use in thetreatment of conditions mediated by the action of ligands for the DP₁,FP, EP₁ and EP₄ prostaglandin (PG) receptors. The compounds of thisinvention are also useful for treating conditions mediated by the actionof ligands for the thromboxane (TP) receptor.

Some embodiments of the present invention include:

1. A compound, that is a 1-[(5-halo or alkyl or fluoroalkyl oralkoxy-2-{(hydrocarbyl or substituted hydrocarbyl)oxy}phenyl)methyl]-(3or 5 alkyl or fluoroalkyl)-1H-pyrazole-4-(carboxylic acid or methylenecarboxylic acid) or an alkyl or aryl ester or sulfonamide thereof. (Aswill be understood by those of ordinary skill in the art, certaincompounds of the invention may be the same but have slightly differentnames. In one example, the compounds may be designated as a “methylenecarboxylic acid' or an “acetic acid”. They are the same, despite thedifferent nomenclature.).

2. The compound of paragraph 1 wherein said halo is selected from thegroup consisting of chloro and bromo.

3. The compound of paragraph 1 wherein said hydrocarbyl is selected fromthe group consisting of alkyl and carbocyclic aryl.

4. The compound of paragraph 3 wherein said hydrocarbyl is selected fromthe group consisting of branched chain alkyl and phenyl.

5. The compound of paragraph 4 wherein said hydrocarbyl is selected fromthe group consisting of branched chain alkyl having from 4 to 7 carbons.

6. The compound of paragraph 1 wherein said compound is a 1-[(5-Chloroor bromo-or trifluoromethyl-2-{hydrocarbyloxy}phenyl)methyl]-(3 or 5methyl)-1H- pyrazole-4-carboxylic acid.

7. The compound of paragraph 6 wherein said hydrocarbyl is selected fromthe group consisting of alkyl and carbocyclic aryl.

8. The compound of paragraph 6 wherein said hydrocarbyl is selected fromthe group consisting of branched chain alkyl and phenyl.

9. The compound of paragraph 6 wherein said hydrocarbyl a branched chainalkyl having from 4 to 7 carbons.

10. The compound of paragraph 1 that is selected from the groupconsisting of:

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-methylenecarboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-1H-pyrazole-4-carboxylicacid;

1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3-propyl-1H-pyrazole-4-carboxylicacid;

1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-propyl-1H-pyrazole-4-carboxylicacid;

1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;

1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid; and,

1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid.

11. A compound having the following formula:

X is O, NR₇ or (CH₂)_(n), wherein n is 0 or an integer of 1 or 2;

Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;

Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;

W is hydrocarbyl or substituted hydrocarbyl;

R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;

R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₄ is selected from the group consisting of H, NH₂, alkyl, nitrogensubstituted alkyl and halogen-substituted alkyl;

R₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₆ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,

R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl.

12. The compound of paragraph 11, wherein R₁ is OH.

13. The compound of paragraph 11, wherein R₂ is selected from the groupconsisting of H, alkyl and halogen-substituted alkyl, e.g.fluoro-substituted alkyl.

14. The compound of paragraph 11, wherein R₄ is selected from the groupconsisting of H, alkyl and halogen-substituted alkyl, e.g.fluoro-substituted alkyl.

15. The compound of paragraph 11, wherein R₁ is X is (CH₂)_(n), whereinn is 0 or 1.

16. The compound of paragraph 11, wherein R₅ is selected from the groupconsisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro,amino, cyano and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.

17. The compound of paragraph 11, wherein R₅ is chloro or bromo.

18. The compound of paragraph 11, wherein R₆ is selected from the groupconsisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro,amino, cyano and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.

19. The compound of paragraph 18, wherein R₆ is H.

20. The compound of paragraph 11, wherein Y is absent, i.e. n is 0.

21. The compound of paragraph 11, wherein Z is O.

22. The compound of paragraph 11, wherein W is selected from the groupconsisting of alkyl, aryl, alkoxy, aryloxy and hydroxy, halogen, nitro,amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy.

23. The compound of paragraph 22, wherein W is selected from the groupconsisting of alkyl, e.g. branched chain alkyl such as 2-ethylbutyl,2-methylpropyl, etc. and carbocyclic aryl, e.g. phenyl.

24. The compound of paragraph 11 that is selected from the groupconsisting of:

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-methylenecarboxylicacid;

1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid; and,

5-amino-1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazole-4-carboxylicacid.

25. A method of making a {1-2-[(hydrocarbyl or substitutedhydrocarbyloxy)-benzyl] 1H-pyrazol- or alkyl-1H-pyrazol)-4-yl }-aceticor carboxylic acid which comprises hydrolyzing the corresponding{1-2-[(hydrocarbyl or substitutedhydrocarbyloxy)-benzyl]1H-pyrazol-4-yl}-acetic or carboxylic acid, alkylester to yield said {1-2-[(hydrocarbyl or substitutedhydrocarbyloxy)-benzyl]1H-pyrazol-4-yl}-acetic or carboxylic acid.

26. The method of paragraph 25 wherein said {1-2-[(hydrocarbyl orsubstituted hydrocarbyloxy)-benzyl]1H-pyrazol-4-yl}-acetic or carboxylicacid is a {1-[halo orhaloalkyl-2-(hydrocarbyloxy)-benzyl]-alkyl-1H-pyrazol-4-yl}-acetic orcarboxylic acid.

27. The method of paragraph 26 wherein said {1-[halo orhaloalkyl-2-(hydrocarbyloxy)-benzyl]-alkyl-1H-pyrazol-4-yl}-acetic orcarboxylic acid is a {1-[5-halo or haloalkyl-2-(branched chain alkyl orphenyloxy)-benzyl]-3 and/or 5-alkyl-1H-pyrazol-4-yl}-acetic orcarboxylic acid.

28. The method of paragraph 27 wherein said halo or haloalkyl isselected from the group consisting of chloro, bromo and trifluoromethyl.

29. The method of paragraph 27 wherein said hydrocarbyl is a branchedchain alkyl having from 4 to 7 carbons.

30. The method of paragraph 28 wherein said branched chain alkyl is2-ethylbutyl.

31. The method of paragraph 27 wherein said 3 and/or 5 alkyl is selectedfrom the group consisting of methyl and n-propyl.

32. The method of paragraph 25 wherein said {1-2-[(hydrocarbyl orsubstituted hydrocarbyloxy)-benzyl] 1H-pyrazol- oralkyl-1H-pyrazol-4-yl}-acetic or carboxylic acid, alkyl ester is a{1-[5-bromo-2-(hydrocarbyloxy)-benzyl]-alkyl-1H-pyrazol-4-yl}-acetic orcarboxylic acid, alkyl ester and said method further comprises the stepof reacting a solution of thecorresponding[1-(5-Bromo-2-hydroxy-benzyl)alkyl-1H-pyrazol-4-yl]-aceticor carboxylic acid alkyl ester with the corresponding hydrocarbylalcohol to obtain said {1-[2-(hydrocarbyloxy)-benzyl]-alkyl-1H-pyrazol-4-yl}-acetic or carboxylic acid, alkylester.

33. The method of paragraph 31 wherein said {1-[2-(hydrocarbyloxy)-benzyl] 1H-pyrazol- or alkyl-1H-pyrazol)--4-yl}-acetic orcarboxylic acid, alkyl ester is a[1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-carboxylic oracetic acid ethyl ester and said method further comprises the steps ofreacting a suspension ofN′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acid tert-butyl esterwith a mixture of CH₂Cl₂ and TFA and removing the volatiles therefrom toobtain a residue, dissolving said residue in absolute EtOH and adding a3-[1-dimethylamino-methylidene]-oxoalkanoic acid ethyl ester to theresulting solution and obtaining a [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-carboxylic oracetic acid ethyl ester.

34. The method of paragraph 32 wherein said3-[1-dimethylamino-methylidene]-oxoalkanoic acid ethyl ester is3-[1-dimethylamino-methylidene]-4-oxo-pentanoic acid ethyl ester toyield the acetic acid ethyl ester.

35. The method of paragraph 32 wherein said3-[1-dimethylamino-methylidene]-oxoalkanoic acid ethyl ester is2-[1-Dimethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid methyl ester toyield the carboxylic acid ethyl ester.

36. The method of paragraph 25 wherein said {1-2-[(hydrocarbyl orsubstituted hydrocarbyloxy)-benzyl] 1H-pyrazol- oralkyl-1H-pyrazol-4-yl}-acetic or carboxylic acid, alkyl ester is a{1-[5-chloro-2-(hydrocarbyloxy)-benzyl]-(1H-pyrazol- oralkyl-1H-pyrazol)-4-yl}-acetic or carboxylic acid, alkyl ester and saidmethod further comprises the steps of reacting a solution of a4-pyrazole or an alkyl-4-pyrazole carboxylate with NaH, under an inertatmosphere, e.g. a N₂ atmosphere, contacting the resulting reactionproduct with a solution of methanesulfonic acid5-chloro-2-(hydrocarbyloxy)-benzyl ester in a polar aprotic solvent,e.g. DMF, to obtain a 1-[5-Chloro-2-(hydrocarbyloxy)-benzyl]-(1H-pyrazol- or alkyl-1H-pyrazol)-4-acetic or carboxylic acid alkylester.

37. The method of paragraph 35 wherein said method further comprises thestep of reacting a solution of[5-Chloro-2-(hydrocarbyloxy)-phenyl]-methanol, di-isopropyl-ethyl amineand methanesulfonic anhydride in CH₂Cl₂ to obtain said methanesulfonicacid 5-chloro-2-(hydrocarbyloxy)-benzyl ester.

38. The method of paragraph 36 wherein said method further comprises thestep of reacting a solution of 5-Chloro-2-(hydrocarbyloxy)-benzaldehyde,MeOH and NaBH₄ under an inert atmosphere, e.g. N₂, to obtainsaid[5-Chloro-2-(hydrocarbyloxy)-phenyl]-methanol.

39. The method of paragraph 38 wherein said method further comprises thestep of reacting a solution of 5-chloro-2-hydroxybenzaldehyde in a polaraprotic solvent, e.g. DMF, under an inert atmosphere, e.g. a N₂atmosphere, at RT with 3-(chloromethyl)pentane, K₂CO₃, andtetrabutylammonium iodide to obtain5-Chloro-2-(hydrocarbyloxy)-benzaldehyde.

40. The method of paragraph 35 wherein said pyrazol-4-yl is a 3 and/or 5alkyl pyrazol-4-yl, e.g. a methyl or propyl pyrazol-4-yl.

41. The method of paragraph 25 wherein said {1-2-[(hydrocarbyl orsubstituted hydrocarbyloxy)-benzyl] 1H-pyrazol- or alkyl-1H-pyrazol-4-yl}-acetic or carboxylic acid, alkyl ester is a{1-[5-trifluoromethyl-2-(hydrocarbyloxy)-benzyl]-alkyl-1H-pyrazol-4-yl}-aceticor carboxylic acid, alkyl ester and said method further comprises thestep of reacting a solution of the corresponding[1-(5- trifluoromethyl-2-hydroxy-benzyl)alkyl-1H-pyrazol-4-yl]-acetic or carboxylic acid alkylester with the corresponding hydrocarbyl alcohol to obtain said{1-[5-trifluoromethyl-2-(hydrocarbyloxy)-benzyl]-alkyl-1H-pyrazol-4-yl}-acetic or carboxylic acid, alkylester.

42. The method of paragraph 41 further comprising the steps of providinga solution of1-(5-Methoxy-2-trifluoromethyl-benzyl)-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester in dry DCM, at 0° C., under an inert atmosphere, e.g. aN₂ atmosphere, a boron tribromide allowing the solution to warm to roomtemperature, quenching the solution with MeOH and refluxing to yield1-(5-Trifluoromethyl-2-hydroxy-benzyl)- methyl-1H-pyrazol-4-ylcarboxylic acid methyl ester.

43. The method of paragraph 42 further comprising the steps of providinga solution of ethyl-4-pyrazole carboxylate in a polar aprotic solvent,e.g. DMF, under an inert atmosphere, e.g. a N₂ atmosphere, at RT, andsequentially adding to said solution, NaH in mineral oil and a solutionof bromomethylsubtituted benzyl5-chloro-2-(2-ethyl-butoxy)-benzyl esterin a polar aprotic solvent, e.g. DMF, pouring the resulting solutioninto water, removing the volatiles and purifying the resulting crudeproduct to yield1-[5-Trifluoromethyl-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylicacid ethyl ester as a 3:2 mixture with its regioisomer.

44. A method comprising administering a compound having the followingformula:

Wherein X is O, NR₅ or (CH₂)_(n), wherein n is 0 or an integer of 1 or2;

Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;

Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;

W is hydrocarbyl or substituted hydrocarbyl;

R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;

R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₄ is selected from the group consisting of H, NH₂, alkyl,nitrogen-substituted alkyl and halogen-substituted alkyl;

R₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₆ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,

R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl.

45. The method of paragraph 44 wherein said compound is administered totreat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases orconditions.

46. The method of paragraph 45 wherein said condition or disease isrelated to inflammation.

47. The method of paragraph 45 wherein said DP1, FP, EP1, TP and/or EP4receptor mediated condition or disease is selected from the groupconsisting of allergic conditions, asthma, allergic asthma, allergicrhinitis, uveitis and related disorders, atherosclerosis, bloodcoagulation disorders, bone disorders, cancer, cellular neoplastictransformations, chronic obstructive pulmonary diseases and other formsof lung inflammation, congestive heart failure, diabetic retinopathy,diseases or conditions requiring a treatment of anti-coagulation,diseases requiring control of bone formation and resorption, fertilitydisorders, gangrene, glaucoma, hyperpyrexia, immune and autoimmunediseases, inflammatory conditions, metastic tumor growth, migraine,mucus secretion disorders, nasal congestion, nasal inflammation,occlusive vascular diseases, ocular hypertension, ocular hypotension,osteoporosis, rheumatoid arthritis, pain, perennial rhinitis, pulmonarycongestion, pulmonary hypotension, Raynaud's disease, rejection in organtransplant and by-pass surgery, respiratory conditions, hirsutism,rhinorrhea, shock, sleep disorders, and sleep-wake cycle disorders.

48. The method of paragraph 45 wherein said compound is administered asa surgical adjunct in ophthalmology for cataract removal and artificiallens insertion, ocular implant procedures, photorefractive radialkeratotomy and other ophthalmogical laser procedures.

49. The method of paragraph 45 wherein said compound is administered asa surgical adjunct in a procedure involving skin incisions, relief ofpain and inflammation and scar formation/keloids post-surgery, fortreating sports injuries and general aches and pains in muscles andjoints.

50. The method of paragraph 45 wherein said DP₁, FP, EP₁, TP, and/or EP₄receptor mediated condition or disease is an EP₁ and/or EP₄ receptormediated condition or disease.

51. The method of paragraph 42 wherein said DP₁, FP, EP₁, TP and/or EP₄receptor mediated condition or disease is an allergic condition.

52. The method of paragraph 51 wherein said condition is dermatologicalallergy.

53. The method of paragraph 51 wherein said condition is an ocularallergy.

54. The method of paragraph 51 wherein said condition is a respiratoryallergy.

55. The method of paragraph 45 wherein said condition or disease isselected from the group consisting of nasal congestion, rhinitis, andasthma.

56. The method of paragraph 45 wherein said condition or disease isrelated to pain.

57. The method of paragraph 45 wherein said condition or disease isselected from the group consisting of arthritis, migraine, and headache.

58. The method of paragraph 45 wherein said condition or disease isassociated with the gastrointestinal tract.

59. The method of paragraph 45 wherein said condition or disease isselected from the group consisting of peptic ulcer, heartburn, refluxesophagitis, erosive esophagitis, non-ulcer dyspepsia, infection byHelicobacter pylori, alrynitis, and irritable bowel syndrome.

60. The method of paragraph 56 wherein said condition or disease isselected from the group consisting of hyperalgesia and allodynia.

61. The method of paragraph 45 wherein said condition or disease isrelated to mucus secretion.

62. The method of paragraph 45 wherein said mucus secretion isgastrointestinal.

63. The method of paragraph 45 wherein said mucus secretion occurs inthe nose, sinuses, throat, or lungs.

64. The method of paragraph 45 wherein said condition or disease isrelated to abdominal cramping.

65. The method of paragraph 45 wherein said condition or disease isirritable bowel syndrome.

66. The method of paragraph 45 wherein said condition or disease is ableeding disorder. 67. The method of paragraph 45 wherein said conditionor disease is a sleep disorder. 68. The method of paragraph 45 whereinsaid condition or disease is mastocytosis. 69. The method of paragraph45 wherein said condition or disease is associated with elevated bodytemperature.

70. The method of paragraph 45 wherein said condition or disease isassociated with ocular hypertension and glaucoma.

71. The method of paragraph 45 wherein said condition or disease isassociated with ocular hypotension.

72. The method of paragraph 45 wherein said condition relates tosurgical procedure to treat pain, inflammation and other unwantedsequelae wherein said surgical procedure includes incision, lasersurgery or implantation.

73. The method of paragraph 45 where said condition is related to painand inflammation and post-surgical scar and keloid formation.

74. A pharmaceutical product comprising a compound having the followingformula:

Wherein X is O, NR₅ or (CH₂)_(n), wherein n is 0 or an integer of 1 or2;

Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;

Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;

W is hydrocarbyl or substituted hydrocarbyl;

R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;

R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₄ is selected from the group consisting of H, NH₂, alkyl,nitrogen-substituted alkyl and halogen-substituted alkyl;

R₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₆ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,

R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl or apharmaceutically acceptable salt or a prodrug thereof, wherein saidproduct is packaged and labeled for the treatment or prevention of adisease or condition selected from the group consisting of uveitis,allergic conditions, asthma, allergic asthma, allergic rhinitis,atherosclerosis, blood coagulation disorders, bone disorders, cancer,cellular neoplastic transformations, chronic obstructive pulmonarydiseases and other forms of lung inflammation, congestive heart failure,diabetic retinopathy, diseases or conditions requiring a treatment ofanti-coagulation, diseases requiring control of bone formation andresorption, fertility disorders, hyperpyrexia, gangrene, glaucoma,hypothermia, immune and autoimmune diseases, inflammatory conditions,metastic tumor growth, migraine, mucus secretion disorders, nasalcongestion, nasal inflammation, occlusive vascular diseases, ocularhypertension, ocular hypotension, osteoporosis, pain, perennialrhinitis, pulmonary congestion, pulmonary hypotension, Raynaud'sdisease, rejection in organ transplant and by-pass surgery, respiratoryconditions, rheumatoid arthritis, rhinorrhea, shock, sleep disorders,sleep-wake cycle disorders, sports injuries, muscle aches and pains, andsurgical adjunct for minimizing pain, inflammation and scar/keloidformation.

75. A pharmaceutical composition comprising a compound having thefollowing formula:

wherein X is O, NR₅ or (CH₂)_(n), wherein n is 0 or an integer of 1 or2;

Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;

Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;

W is hydrocarbyl or substituted hydrocarbyl;

R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;

R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₄ is selected from the group consisting of H, NH₂, alkyl,nitrogen-substituted alkyl and halogen-substituted alkyl;

R₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₆ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,

R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkylor apharmaceutically acceptable salt or a prodrug thereof, and apharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIGS. 1, 2 and 3 show the reaction schemes for the preparation of thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The following terms are used to define the disclosed invention.

“Hydrocarbyl” refers to a hydrocarbon radical having only carbon andhydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20carbon atoms, more preferably from 1 to 12 carbon atoms and mostpreferably from 1 to 7 carbon atoms.

“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one ormore, but not all, of the hydrogen and/or the carbon atoms are replacedby a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radicalincluding a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g.fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.

“Methylenyl” refers to a —CH₂— linking group. “Alkyl” refers to astraight-chain, branched or cyclic saturated aliphatic hydrocarbon.Preferably, the alkyl group has 1 to 12 carbons. More preferably, it isan alkyl of from 4 to 10 carbons, most preferably 4 to 8 carbons.Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl groupmay be optionally substituted with one or more substituents are selectedfrom the group consisting of hydroxyl, cyano, alkoxy, ═O, ═S, NO₂,halogen, dimethyl amino, and SH.

“Cycloalkyl” refers to a cyclic saturated aliphatic hydrocarbon group.Preferably, the cycloalkyl group has 3 to 12 carbons. More preferably,it has from 4 to 7 carbons, most preferably 5 or 6 carbons.

“Aryl” refers to an aromatic group which has at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl and biaryl groups. The aryl group may be optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl, hydroxyl, halogen, COOR⁷, NO₂, CF₃, N(R⁷)₂,CON(R⁷)₂, SR⁷, sulfoxy, sulfone, CN and OR⁷, wherein R⁷ is selected fromthe group consisting of H, hydrocarbyl and substituted hydrocarbyl, e.g.carbocyclic aryl and alkyl

“Carbocyclic aryl” refers to an aryl group wherein the ring atoms arecarbon.

“Heteroaryl or heterocyclic aryl” refers to an aryl group having from 1to 3 heteroatoms as ring atoms, the remainder of the ring atoms beingcarbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus,heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl,N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.Preferably, the heteroaryl group has from 2 to 10 carbons. Morepreferably, it has from 3 to 10 carbons, most preferably 3 carbons.

Pharmaceutical compositions contemplated herein include compositionswherein the active ingredient is contained in an effective amount, i.e.,in an amount effective to achieve its intended purpose. An “effectiveamount” is an amount sufficient to accomplish a stated purpose (e.g.,achieve the effect for which it is administered, treat a disease, reduceone or more symptoms of a disease or condition). An example of an“effective amount” is an amount sufficient to contribute to thetreatment, prevention, or reduction of a symptom or symptoms of adisease, which can be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). Theactual amount effective for a particular application will depend, interalia, on the condition being treated.

“Treatment” , “treat” or “treating” can refer to curing any disease orcondition or reducing or alleviating the symptoms of the disease orcondition.

The present invention provides compounds having the general formula:

Wherein X is O, NR₇ or (CH₂)_(n), wherein n is 0 or an integer of 1 or2;

Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;

Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;

W is hydrocarbyl or substituted hydrocarbyl;

R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;

R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₄ is selected from the group consisting of H, NH₂, alkyl,nitrogen-substituted alkyl and halogen-substituted alkyl;

R₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₆ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl;

Preferably, R₁ is OH;

Preferably, R₂ is selected from the group consisting of H, alkyl andhalogen-substituted alkyl, e.g. fluoro-substituted alkyl;

Preferably, R4 is selected from the group consisting of H, alkyl andhalogen-substituted alkyl, e.g. fluoro-substituted alkyl;

Preferably, X is (CH₂)n, wherein n is 0 or 1;

Preferably, R₅ is selected from the group consisting of H, hydroxy,alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy oraryloxy. More preferably R₅ is chloro or bromo;

Preferably, R₆ is selected from the group consisting of H, hydroxy,alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy oraryloxy. More preferably R₆ is H;

Preferably, Y is absent, i.e. n is 0;

Preferably, Z is O;

Preferably, W is selected from the group consisting of alkyl, aryl,alkoxy, aryloxy and hydroxy, halogen, nitro, amino and cyano-substitutedalkyl, aryl, alkoxy or aryloxy.

More preferably, W is selected from the group consisting of alkyl, e.g.branched chain alkyl such as 2-ethylbutyl, 2-methylpropyl, etc. andcarbocyclic aryl, e.g. phenyl.

As shown in the Examples, below, preferably, certain of the preferredcompounds of the present invention are prepared by a method of making a1-[(hydrocarbyloxy)-benzyl]-1H-pyrazole-4-carboxylic acid whichcomprises the steps of:

(1) adding a reducing agent, e.g. NaH in mineral oil, to a solution ofalkyl-4-pyrazole carboxylate dissolved in a polar aprotic solvent, e.g.DMF, under an inert atmosphere and stirring at RT;

(2) adding to the resulting mixture of step(1), a solution ofmethanesulfonic acid 2-(hydrocarbyl)-benzyl ester in a polar aproticsolvent, e.g. DMF, and stirring the resulting mixture for a sufficienttime, e.g. 16 hours, to yield a reaction product comprising a1-[2-(hydrocarbyl)-benzyl]-1H-pyrazole-4-carboxylic acid alkyl ester;and,

(3) hydrolyzing the reaction product of step(2) comprising said142-(hydrocarbyl)-benzyl]-1H-pyrazole-4-carboxylic acid alkyl ester; andrecovering a 1-[2-(hydrocarbyl)-benzyl]-1H-pyrazole-4-carboxylic acid.

An example of the above preferred method of making the preferredcompounds, as shown in Example 4, below, is a method of making1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylic acidwhich comprises the steps of:

(1) adding NaH in mineral oil to a solution of ethyl-4-pyrazolecarboxylate dissolved in a polar aprotic solvent under an inertatmosphere at RT and stirring;

(2) adding to the resulting mixture of step(1), a solution ofmethanesulfonic acid 5-chloro-2-(2-ethyl-butoxy)-benzyl ester dissolvedin a polar aprotic solvent and stirring the resulting mixture atconditions sufficient to yield1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylic acidethyl ester;

(3) hydrolyzing the reaction product of step(2) to obtain145-chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylic acid;and,

(4) recovering 14-2-(hydrocarbyl)-benzyl]-1H-pyrazole-4-carboxylic acid.

Said 5-chloro-2-(2-ethyl-butoxy)-phenyl]-methanol may be obtained bycooling a solution of 5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde in MeOHto +5° C. under an inert atmosphere and adding NaBH and allowing theresulting mixture to warm to RT over 2 hours.

Said 5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde, 10 may be obtained byadding a solution of 3-(chloromethyl)pentane, K₂CO andtetrabutylammonium iodide in a polar aprotic solvent to a solution of5-chloro-2-hydroxybenzaldehyde in a polar aprotic solvent under an inertatmosphere at RT and stirring the resulting mixture at 120° C. for atime sufficient to a obtain a reaction product comprising5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde.

Methanesulfonic acid 5-chloro-2-(2-ethyl-butoxy)-benzyl ester may beobtained by reacting a solution of[5-Chloro-2-(2-ethyl-butoxy)-phenyl]-methanol 11, di-isopropyl-ethylamine and methanesulfonic anhydride under an inert atmosphere atconditions sufficient to yield said methanesulfonic acid5-chloro-2-(2-ethyl-butoxy)-benzyl ester.

The corresponding bromo compound is prepared in Example 2 by ananalogous method.

Said polar aprotic solvent may be selected from the group consisting ofdichloromethane, tetrahydrofurane, ethylacetate, acetone,dimethylformamide, and acetonitrile.

The following examples are intended to illustrate the present invention.

The reagents and conditions used in FIGS. 1, 2, 3 and the Examples maybe abbreviated as follows:

Ac is acetyl;

DCM is dichloromethane;

RT is room temperature;

Ph is phenyl;

DMF is dimethylformamide;

Et is ethyl;

THF is tetrahydrofuran; and,

HEPES is 4- (2-hydroxyethyl)-1-piperazineethanesulfonic acid).

EXAMPLE 1{1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-5-METHYL-1H-PYRAZOL-4-YL}-ACETICACID, 4

Step 1 N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acid tert-butylester 1

A solution of 5-bromo-2-hydroxybenzaldehyde (10 g g 50 mmol),tert-butylcarbazate(6.7 g, 52 mmol) and acetic acid (3 mL, 52 mmol) inCH₂Cl₂ (200 mL) was stirred under N₂ atmosphere for 60 min at RT. Thensodium triacetoxyborohydride (34 g, 159 mmol) was added portion wise andthe resulting mixture was stirred at RT overnight. The reaction wasquenched with 2 M HCl (100 mL) and stirred at RT for 1 h. The reactionmixture was partitioned between water (100 mL) and CH₂Cl₂ (250 mL). Theorganic layer was washed with sat. NaHCO₃ and brine (100 mL each), dried(MgSO₄) and evaporated to dryness to give hydrazine 1 as a white solid,13 g (82%).

¹H-NMR(CDCl₃, 300 MHz) δ7.29 (dd, H ArH, J=2.4, 8.6 Hz), 7.17 (d, 1H,J=2.4 Hz, ArH), 6.80 (d, 1H, J=8.6 Hz, ArH), 1.49 (s, 9H, —C(CH₃)₃).

LC-MS: m/z 318 M+H⁺

Step 2 [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]aceticacid ethyl ester, 2

A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acidtert-butyl ester 1 1 g (3.1 mmol) in a mixture of CH₂Cl₂ (8 mL) and TFA(8 mL) was stirred at RT for 2 hours. The volatiles were removed invacuo. The residue was dissolved in abs. EtOH (7 mL) and added to3-[1-dimethylamino-methylidene]-4-oxo-pentanoic acid ethyl ester (4.8mmol) at RT. The resulting mixture was stirred at RT for 1 hour,refluxed for 2 h, let cool down and stirred at RT for 16 h. The oilyresidue obtained after removing the volatiles in vacuo was purified byMPLC (10 g SiO₂ cartridge, eluent 90% iso-hexane—10% EtOAc) to give 0.18g of [1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acidethyl ester, 2.

¹H-NMR(CDCl₃, 300 MHz) δ 7.45 (s, 1H, ArH), {tilde over (7)}33 (dd, 1H,ArH), 7727 (dd, 1H, ArH), 6.87 (dd, 1H, ArH), 5.11 (s, 2H, ArCH₂), 4.16(q, 2H, —CH₂CH₃), 3.39 (s, 2H, ArCH₂), 2.34 (s, 3H, CH₃) 1.27 (t, 3H,—CH₂CH₃).

LC-MS: m/z 354 M+H⁺

Step 3{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-aceticacid ethyl ester, 3

A solution of[1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acidethyl ester, 2, (0.18 g g 0.51 mmol), triphenylphosphine (0.26 g, 1.02mmol), di-tert-butylazodicarboxylate (0.23 g, 1.02 mmol) and2-ethylbutan-1-ol (0.116 ml, 1.02 mmol) in a mixture of THF (1 mL) andtoluene (2 ml) was at 120° C. on microwave for 20 min. The volatileswere removed in vacuo. The crude product was purified on silica to yield{1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-aceticacid ethyl ester, 3.

a pale yellow oil, 0.1 g (45%).

¹H-NMR(CDCl₃, 300 MHz) δ 7.49 (s, 1H, ArH), 7.32 (dd, 1H ArH),.6.76 (4,1H, ArH), 6.65 (dd, 1H, ArH), 5.27 (s, 2H, ArCH₂), 4.17 (q, 2H,—CH₂CH₃), 3.90 (dd, 2H, CH₂), 3.45 (s, 2H, ArCH₂),), 2.16 (s, 3H, CH₃),1.71 (m, 1H, CH), 1.50 (m, 4H, CH₂), 1.28 (t, 3H, —CH₂CH₃), 0.96 (t, 6H,CH₃).

LC-MS: m/z 438 M+H⁺

Step 4{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-aceticacid, 4

To a solution of{1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-aceticacid ethyl ester, 3, 0.1 g (0.22 mmol) in a mixture of THF (1 mL) andmethanol (0.5 ml) was added a solution of LiOH (0.12 g in 1 ml H₂O). Theresulting mixture was heated at 100° C. on microwave for 20 minutes. Themixture was poured into water (20 mL) and extracted with EtOAc (3×15mL). The organic layers were combined, washed with brine (30 mL), dried(MgSO₄) and the volatiles removed in vacuo. The crude product waspurified on silica to yield 7.4 mg (10%) of{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-aceticacid, 4 as a white solid.

¹H-NMR (CDCl₃, 300 MHz) δ 7.50(, 1H,ArH), 7.32 (dd, 1H, ArH), 6.76 (d,1H ArH), 6.70 (dd, 1H, ArH), 5.27 (s, 2H, ArCH₂), 3.90 (dd, 2H, CH₂),3.50 (s, 2H, ArCH₂), 2.16 (s, 3H, CH₃), 1.70 (m, 1H, CH), 1.50 (m, 4H,CH₂), 0.96 (t, 6H, CH₃).

LC-MS: m/z 410 M+H⁺

EXAMPLE 21-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-5-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 7

Step 1 1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-4-carboxylicacid methyl ester, 5

A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acidtert-butyl ester 1 2 g (6.3 mmol) in a mixture of CH₂Cl₂ (8 mL) and TFA(8 mL) was stirred at RT for 2 hours. The volatiles were removed invacuo. The residue was dissolved in abs. EtOH (7 mL) and added to2-[1-Dimethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid methyl ester (12mmol) at RT. The resulting mixture was stirred at RT for 1 hour,refluxed for 2 h, let cool down and stirred at RT for 16 h. The oilyresidue obtained after removing the volatiles in vacuo was purified byMPLC (10 g SiO₂ cartridge, eluent 90% iso-hexane—10% EtOAc) to give 0.38g of 1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-4-carboxylic acidmethyl ester, 5 and1-(5-Bromo-2-hydroxy-benzyl)-3-methyl-1H-pyrazole-4-carboxylic acidmethyl ester 6 as a mixture.

LC-MS: m/z 326 M+H⁺

Step 21-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-4-carboxylicacid methyl ester, 6

The title compound was prepared following the method in Example 1, Step3.

Step 31-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-4-carboxylicacid, 7

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.02 (s, 1H, ArH), 7.37 (dd, 1H, ArH), 6.83(d, 1H, ArH), 6.78 (d, 1H, ArH), 5.21 (s, 2H, ArCH₂), 3.90 (d, 2H, CH₂),2.53 (s, 3H, CH₃), 1.71 (m, 1H, CH), 1.48 (m, 4H, CH₂), 0.96 (t, 6H,CH₃).

LC-MS: m/z 396 M+H⁺

EXAMPLE 3 1-(5-BROMO-2-HYDROXY-BENZYL)-3-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID METHYL ESTER, 9

Step 11-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazole-4-carboxylicacid methyl ester, 8

The title compound was prepared using the mixture from Example 2, Step 1following the method in Example 1, Step 3.

¹H-NMR (CDCl₃, 300 MHz) δ 7.94 (s, 1H, ArH), 7.35 (dd, 1H, ArH), 6.78(d, 1H, ArH), 6.77 (s, 1H, ArH), 5.29 (s, 2H, ArCH₂), 3.90 (d, 2H, CH₂),3.85 (s, 3H, CH₃), 2.51 (s, 3H, CH₃), 1.71 (m, 1H, CH), 1.49 (m, 4H,CH₂), 0.95 (t, 6H, CH₃).

LC-MS: m/z 410 M+H⁺.

Step 2 1-(5-Bromo-2-hydroxy-benzyl)-3-methyl-1H-pyrazole-4-carboxylicacid methyl ester, 9

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 7.84 (s, 1H, ArH), 7.42 (dd, 1H, ArH), 7.25(d, 1H, ArH), 6.80 (d, 1H, ArH), 5.22 (s, 2H, ArCH₂), 3.87 (d, 2H, CH₂),2.50 (s, 3H, CH₃), 1.67 (m, 1H, CH), 1.44 (m, 4H, CH₂), 0.92 (t, 6H,CH₃).

LC-MS: m/z 396 M+H⁺.

EXAMPLE 41-[5—CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-PYRAZOLE-4-CARBOXYLIC ACID, 14

Step 1 5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde, 10

To a solution of 5-chloro-2-hydroxybenzaldehyde, 2.1 g (13.4 mmol) DMF(50 mL) under N₂ atmosphere at RT was added 3-(chloromethyl)pentane(1.92 g 15.6 mmol), K₂CO₃ (4.5 g, 32.6 mmol) and tetrabutylammoniumiodide (0.35 g, 0.9 mmol). The resulting mixture was stirred at 120° C.for 5 hours. The mixture was partitioned between water (80 ml) and EtOAc(80 ml). The organic layer was washed with water (80 ml) followed bybrine (80 ml), dried over (Na₂SO₄), filtered and the volatiles wereremoved in vacuo. The crude product was purified on silica to yield toyield 2.83 g of 5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde, 10.

1H-NMR, (CDCl₃, 300 MHz) δ 10.46 (s, 1H ArCHO,), 7.80 (d, 1H, ArH,),7.49 (dd, 1H, ArH), 6.97 (d, 1H, ArH), 3.99 (d, 2H, CH₂), 1.75 (m, 1H,CH), 1.52 (m, 4H, CH₂), 0.97 (t, 6H, CH₃).

LC-MS: m/z 241 M+H⁺.

Step 2 [5-Chloro-2-(2-ethyl-butoxy)-phenyl]methanol, 11

A solution of 5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde, 10, (2.83 g 11.8mmol), MeOH (50 mL) was cooled to +5° C. under N₂ atmosphere and NaBH₄(0.54 g, 14.2 mmol) was added. The mixture was allowed to warm to RTover 2 hours and the volatiles were removed in vacuo. The reactionmixture was partitioned between water and CH₂Cl₂. The organic layer waswashed with sat. brine, dried (Na₂SO₄) and evaporated to dryness to give2.61 g of 5-chloro-2-(2-ethyl-butoxy)-phenyl]-methanol, 11 as a paleyellow oil.

¹H-NMR (CDCl₃, 300 MHz) δ 7.30 (d, 1H, ArH,), 7.22 (dd, 1H, ArH), 6.82(d, 1H, ArH), 4.68 (d, 2H, CH₂), 3.91 (d, 2H, CH₂), 2.22 (t, 1H, CH₂OH),1.71 (m, 1H, CH), 1.50 (m, 4H, CH₂), 0.96 (t, 6H, CH₃).

LC-MS : m/z 243 M+H⁺.

Step 3 Methanesulfonic acid 5-chloro-2-(2-ethyl-butoxy)-benzyl ester, 12

A solution of [5-Chloro-2-(2-ethyl-butoxy)-phenyl]-methanol, 11, (0.3 gg 1.24 mmol), di-isopropyl-ethyl amine (0.24 mL, 1.36 mmol) andmethanesulfonic anhydride (0.24 g 1.36 mmol) in CH₂Cl₂ (8 mL) wasstirred under N₂ atmosphere at RT for 2 hours. The reaction mixture waspartitioned between water and CH₂Cl₂. The organic layer was washed withsat. brine, dried (MgSO₄) and evaporated to dryness to give mesylate 12,0.39 g.

¹H-NMR (CDCl₃, 300 MHz) δ 7.38 (d, 1H, ArH,), 7.32 (dd, 1H, ArH), 6.86(d, ArH), 5.26 (d, 2H, CH₂), 3.90 (d, 2H, CH₂), 3.01 (s, 3H, CH₃), 1.71(m, 1H, CH), 1.50 (m, 4H, CH₂), 0.95 (t, 6H, CH₃).

Step 4 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylicacid ethyl ester, 13

To a solution of ethyl-4-pyrazole carboxylate, 0.094 g (0.67 mmol) DMF(5 mL) under N₂ atmosphere at RT was added NaH (0.033 g 0.81 mmol, 60%in mineral oils). The resulting mixture was stirred for 30 minutes. Asolution of Methanesulfonic acid 5-chloro-2-(2-ethyl-butoxy)-benzylester, 12, in DMF (2 mL) was the added and the mixture was stirred for16 hours. The mixture was poured into water and the volatiles wereremoved in vacuo. The crude product was purified on silica to yield toyield 0.1 g of1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylic acidethyl ester, 13.

¹H-NMR (CDCl₃, 300 MHz) δ 7.94 (s, 1H, ArH), 7.87 (s, 1H, ArH), 7.27(dd, 1H, ArH), 7.08 (d, 1H, ArH), 6.84 (d, 1H, ArH), 5.29 (s, 2H,ArCH₂), 4.30 (q, 2H, CH₃CH₂), 3.88 (d, 2H, CH₂), 1.67 (m, 1H, CH), 1.47(m, 4H, CH₂), 1.35 (t, 3H, CH₂CH₃), 0.93 (t, 6H, CH₃). LC-MS: m/z 365M+H⁺.

Step 5 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylicacid, 14

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.00 (s, 1H, ArH), 7.93 (s, 1H, ArH), 7.29(dd, 1H, ArH), 7.14 (d, 1H, ArH), 6.85 (d, 1H, ArH), 5.31 (d, 2H,ArCH₂), 3.88 (d, 2H, CH₂), 1.67 (m, 1H, CH), 1.43 (m, 4H, CH₂), 1.35 (t,3H, CH₂CH₃), 0.92 (t, 6H, CH₃).

LC-MS: m/z 337 M+H⁺.

EXAMPLE 51-[5—CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-3,5-DIMETHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 16

Step 11-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-3,5-dimethyl-1H-pyrazole-4-carboxylicacid ethyl ester, 15

The title compound was prepared following the method in Example 4, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 7.18 (dd, 1H, ArH), 6.81 (d, 1H, ArH), 6.55(d, 1H, ArH), 5.23 (d, 2H, ArCH₂), 4 .14 (q, 2H, CH₃CH₂), 3.90 (d, 2H,CH₂), 2.47 (s, 3H, CH₃), 2.45 (s, 3H, CH₃), 1.71 (m, 1H, CH), 1.50 (m,4H, CH₂), 1.38 (t, 3H, CH₂CH₃), 0.95 (t, 6H, CH₃). LC-MS: m/z 393 M+H⁺.

Step 21-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-3,5-dimethyl-1H-pyrazole-4-carboxylicacid, 16

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 7.20 (dd, 1H, ArH), 6.82 (d, 1H, ArH), 6.62(d, 1H, ArH), 5.26 (s, 2H, ArCH₂), 3.91 (d, 2H, CH₂), 2.51 (s, 3H, CH₃),2.50 (s, 3H, CH₃), 1.72 (m, 1H, CH), 1.50 (m, 4H, CH₂), 1.38 (t, 3H,CH₂CH₃), 0.96 (t, 6H, CH₃).

LC-MS: m/z 365 M+H⁺.

EXAMPLE 61-[5—CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-3-PROPYL-1H-PYRAZOLE-4-CARBOXYLICACID, 18

Step 11-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-3-propyl-1H-pyrazole-4-carboxylicacid ethyl ester, 17

The title compound and its region-isomer (2:1 mixture) were preparedfollowing the method in Example 4, Step 4. The mixture was in subsequentstep.

LC-MS: m/z 407 M+H⁺.

Step 21-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-3-propyl-1H-pyrazole-4-carboxylicacid, 18

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.02 (s, 1H, ArCOOH), 7.22 (dd, 1H, ArH), 7.06(d, 1H, ArH), 6.83 (d, 1H, ArH), 6.71 (d, 1H, ArH), 5.32 (d, 2H, ArCH₂),3.91 (d, 2H, CH₂), 2.93 (t, 2H, ArCH₂CH₂), 1.83 (m, 1H, CH), 1.56 (m,2H, CH₂CH₂), 1.50 (m, 4H, CH₂), 0.96 (t, 6H, CH₃), 0.95 (t, 3H, CH₂CH₃).

LC-MS: m/z 379 M+H⁺.

EXAMPLE 71-[5—CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-5-PROPYL-1H-PYRAZOLE-4-CARBOXYLICACID, 20

Step 11-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-propyl-1H-pyrazole-4-carboxylicacid ethyl ester, 19

The title compound and its region-isomer (2:1 mixture) were preparedfollowing the method in Example 4, Step 4. The mixture was used insubsequent step.

LC-MS: m/z 407 M+H⁺.

Step 21-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-propyl-1H-pyrazole-4-carboxylicacid, 20

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 7.83 (d, 1H, ArH), 7.27 (dd, 1H, ArH), 7.06(d, 1H, ArH), 6.84 (d, 1H, ArH), 5.24 (s, 2H, ArCH₂), 3.88 (d, 2H, CH₂),2.88 (t, 2H, ArCH₂CH₂), 1.74 (m, 2H, CH₂CH₂), 1.66 (m, 1H, CH), 1.43 (m,4H, CH₂), 0.99 (t, 3H, CH₂CH₃), 0.91 (t, 6H, CH₃).

LC-MS: m/z 379 M+H⁺.

EXAMPLE 81-[2-(2-ETHYL-BUTOXY)-5-TRIFLUOROMETHYL-BENZYL]-5-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 25

Step 1 2-Bromomethyl-1-methoxy-4-trifluoromethyl-benzene, 21

To a solution of 2-methoxy-5-trifluorobenzyl alcohol, 1 g (4.85 mmol)DCM (20 mL) under N₂ atmosphere at RT was added PBr₃ (5.82 mL, 5.82mmol, 1M in DCM). The resulting mixture was stirred for 16 hours. Thereaction mixture was quenched with saturated NaHCO₃ and partitionedbetween aqueous phase and CH₂Cl₂. The organic layer was washed with sat.brine, dried (MgSO₄) and evaporated to dryness to give 1.1 g of2-bromomethyl- 1 -methoxy-4-trifluoromethyl-benzene, 21.

¹H-NMR (CDCl₃, 300 MHz) δ 7.61 (s, 1H, ArH,), 7.58 (d, 1H, ArH), 6.97(d, 1H, ArH), 4.56 (d, 2H, CH₂), 3.97 (d, 2H, CH₂).

LC-MS: m/z 270 M+H⁺.

Step 21-(2-Methoxy-5-trifluoromethyl-benzyl)-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester, 22

To a solution of ethyl-4-pyrazole carboxylate, 1.1 g (4.09 mmol) in DMF(37 mL) under N₂ atmosphere at RT was added NaH (0.22 g, 5.32 mmol, 60%in mineral oils). The resulting mixture was stirred for 30 minutes. Asolution of 2-bromomethyl-1-methoxy-4-trifluoromethyl-benzene 21 in DMF(2 mL) (0.69 g, 4.5 mmol) was then added and the mixture was stirred for16 hours. The mixture was poured into water and the volatiles wereremoved in vacuo. The crude product was purified on silica to yield 1 gof 1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazole-4-carboxylic acidethyl ester, 22 as a 3:2 mixture with its regioisomer. The mixture wasused in subsequent step.

LC-MS: m/z 343 M+H⁺.

Step 31-(2-Hydroxy-5-trifluoromethyl-benzyl)-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester, 23

To a solution of1-(2-Methoxy-5-trifluoromethyl-benzyl)-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester, 22, 0.2 g (0.60 mmol) in dry DCM (25 ml) under N₂ atmat 0° C., 4.4 ml of boron tribromide (1M in DCM) was added. The solutionwas allowed to warm to room temperature. The mixture was stirred for 24hours, quenched with MeOH and refluxed for 3 hours. Cooled to roomtemperature, water was added, extracted with EtOAc and wash with brine.After drying over MgSO₄ solvents were removed in vacuo and the crudeproduct was purified on silica to yield 0.18 g of1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methylester, 23 as a 3:2 mixture with its regio isomer. The mixture was usedin subsequent step.

LC-MS: m/z 329 M+H⁺.

Step 41-[2-(2-Ethyl-butoxy)-5-trifluoromethyl-benzyl]-5-methyl-1H-pyrazole-4-carboxylicacid, ethyl ester, 24

The title compound was prepared following the method in Example 1, Step3, as a 3:2 mixture with its regioisomer. The mixture was used insubsequent step.

LC-MS: m/z 413 M+H⁺.

Step 51-[2-(2-Ethyl-butoxy)-5-trifluoromethyl-benzyl]-5-methyl-1H-pyrazole-4-carboxyliacid, 25

The title compound was prepared following the method in Example 1, Step4. The title isomer was separated from the mixture by RP-HPLC.

¹H-NMR (CDCl₃, 300 MHz) δ 8.01 (s, 1H, ArH), 7.54 (m, 1H, ArH), 7.00 (m,1H, ArH), 6.98 (m, 1H, ArH), 5.34 (s, 2H, ArCH₂), 3.98 (d, 2H, CH₂),2.54 (s, 3H, CH₃), 1.74 (m, 1H, CH), 1.49 (m, 4H, CH₂), 0.96 (t, 6H,CH₃).

LC-MS: m/z 385 M+H⁺

EXAMPLE 91-[2-(2-ETHYL-BUTOXY)-5-TRIFLUOROMETHYL-BENZYL]-3-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 26

The title compound was prepared from the product of Example 8 step 4following the method in Example 1, Step 4. The title isomer wasseparated from the mixture by RP-HPLC.

¹H-NMR (CDCl₃, 300 MHz) δ 7.84 (s, 1H, ArH), 7.60 (m, 1H, ArH), 7.41 (m,1H, ArH), 6.99 (d, 1H, ArH), 5.28 (s, 2H, ArCH₂), 3.95 (d, 2H, CH₂),2.47 (s, 3H, CH₃), 1.69 (m, 1H, CH), 1.45 (m, 4H, CH₂), 0.92 (t, 6H,CH₃).

LC-MS: m/z 385 M+H⁺

EXAMPLE 101-[5—CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-5-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 28

Step 11-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester, 27

The title compound was prepared following the method in Example 4, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.01 (s, 1H, ArH), 7.20 (dd, 1H, ArH), 6.82(d, 1H, ArH), 6.61 (d, 1H, ArH), 5.29 (s, 2H, ArCH₂), 4.32 (q, 2H,CH₃CH₂), 3.90 (d, 2H, CH₂), 2.50 (s, 3H, CH₃), 1.71 (m, 1H, CH), 1.49(m, 4H, CH₂), 1.38 (t, 2H, CH₃CH₂), 0.96 (t, 6H, CH₃).

LC-MS: m/z 379 M+H⁺

Step 21-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-4-carboxylicacid, 28

The title compound was prepared following the method in Example 1, Step4.

¹H-NMR (CDCl₃, 300 MHz) δ 8.03 (s, 1H, ArH), 7.23 (dd, 1H, ArH), 6.83(d, 1H, ArH), 6.69 (d, 1H, ArH), 5.31 (s, 2H, ArCH₂), 3.92 (d, 2H, CH₂),2.53 (s, 3H, CH₃), 1.72 (m, 1H, CH), 1.49 (m, 4H, CH₂), 0.96 (t, 6H,CH₃).

LC-MS: m/z 351 M+H⁺

EXAMPLE 111-(5—CHLORO-2-ISOBUTOXY-BENZYL)-5-METHYL-1H-PYRAZOLE-4-CARBOXYLIC ACID,29

The title compound was prepared following the methods described forExample 8 and using the appropriate starting materials and reagents

¹H-NMR (CDCl₃, 300 MHz) δ 8.05 (s, 1H, ArH), 7.20 (dd, 1H, ArH), 6.80(d, 1H, ArH), 6.70 (d, 1H, ArH), 5.31 (s, 2H, ArCH₂), 3.78 (d, 2H, CH₂),2.55 (s, 3H, CH₃), 2.15 (m, 1H, CH), 1.03 (d, 6H, CH₃).

LC-MS: m/z 323 M+H⁺

EXAMPLE 121-(5—CHLORO-2-CYCLOPENTYLMETHOXY-BENZYL)-5-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 30

The title compound was prepared following the methods described forExample 8 and using the appropriate starting materials and reagents

¹H-NMR (DMSO, 300 MHz) δ 7.55 (s, 1H, ArH), 7.33 (dd, 1H, ArH), 7.05 (d,1H, ArH), 6.80 (m, 1H, ArH), 5.25 (s, 2H, ArCH₂), 3.90 (d, 2H, CH₂),2.55 (s, 3H, CH₃), 2.27 (m, 1H, CH), 1.75 (m, 2H, CH₂CH₂), 1.6 (m, 4H,—CH₂—CH₂—), 1.30 (m, 2H, —CH₂—CH₂—).

LC-MS: m/z 349 M+H⁺

EXAMPLE 131-(5-BROMO-2-ISOBUTOXY-BENZYL)-5-METHYL-1H-PYRAZOLE-4-CARBOXYLIC ACID,31

The title compound was prepared following the methods described forExample 8 and using the appropriate starting materials and reagents.

¹H-NMR (CDCl₃, 300 MHz) δ 8.03 (s, 1H, ArH), 7.35 (dd, 1H, ArH), 6.87(s, 1H, ArH), 6.75 (d, 1H, ArH), 5.31 (s, 2H, ArCH₂), 3.75 (d, 2H, CH₂),2.55 (s, 3H, CH₃), 2.15 (m, 1H, CH), 1.03 (d, 6H, CH₃).

LC-MS: m/z 369 M+H⁺

EXAMPLE 141-[5-BROMO-2-(2,2-DIMETHYL-PROPDXY)-BENZYL]-5-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 32

The title compound was prepared following the methods described forExample 8 and using the appropriate starting materials and reagents.

¹H-NMR (CDCl₃, 300 MHz) δ 8.05 (s, 1H, ArH), 7.35 (dd, 1H, ArH), 6.80(s, 1H, ArH), 6.75 (d, 1H, ArH), 5.40 (s, 2H, ArCH₂), 3.65 (s, 2H, CH₂),2.52 (s, 3H, CH₃), 1.05 (s, 9H, CH₃).

LC-MS: m/z 383 M+H⁺

EXAMPLE 151-[2-(2-ETHYL-BUTOXY)-5-TRIFLUOROMETHOXY-BENZYL]-5-METHYL-1H-PYRAZOLE-4-CARBOXYLICACID, 33

The title compound was prepared following the methods described forExample 8 and using the appropriate starting materials and reagents.

¹H-NMR (CDCl₃, 300 MHz) δ 8.05 (s, 1H, ArH), 7.15 (dd, 1H, ArH), 6.90(d, 1H, ArH), 6.60 (d, 1H, ArH), 5.32 (s, 2H, ArCH₂), 3.95 (d, 2H, CH₂),2.55 (s, 3H, CH₃), 1.75 (m, 1H, CH), 1.52 (q, 4H, CH₂), 1.00 (t, 6H,CH₃).

LC-MS: m/z 401 M+H⁺

EXAMPLE 165-AMINO-1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-PYRAZOLE-4-CARBOXYLICACID, 36

Step 1 5-Amino-1-(5-bromo-2-hydroxy-benzyl)-1H-pyrazole-4-carboxylicacid, 34

A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acidtert-butyl ester 1 (1 g, 3.1 mmol) in a mixture of CH₂Cl₂ (8 mL) and TFA(8 mL) was stirred at RT for 2 hours. The volatiles were removed invacuo. The residue was dissolved in abs. EtOH (15 mL) andethyl-2-cyano-3-ethoxyacrylate (0.55 g, 3.3 mmol) was added at RT. Theresulting mixture was refluxed for 6 h, let cool down and stirred at RTfor 16 h.

The white solid residue obtained was suspended with EtOAc (10 ml)volatiles were removed in vacuo. The remaining oily residue wastriturated with ether, collected and washed once with ether to give 0.3g of the title compound as a white solid.

¹H-NMR(DMSO-D₆, 300 MHz) δ 10.17 (s, 1H, ArOH), 7.53 (s, 1H, ArH), 7.27(dd, 1H, ArH), 6.80 (d, 1H, ArH), 6.71 (d, 1H, ArH), 6.33 (s, 2H,ArNH₂), 5.05 (s, 2H, ArCH₂), 4.17 (q, 2H, —CH₂CH₃), 1.25 (t, 3H,—CH₂CH₃).

LC-MS: m/z 340,342 M+H⁺

Step 25-amino-1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazole-4-carboxylicacid ethyl ester, 35

The title compound was prepared following the method in Example 1, Step3.

¹H-NMR(CDCl₃, 300 MHz) δ 7.67 (s, 1H, ArH), 7.39 (dd, 1H, ArH), 7.26 (d,1H, ArH), 6.82 (d, 1H, ArH), 5.23 (s, 2H, ArNH₂), 5.10 (s, 2H, ArCH₂),4.28 (q, 2H, —CH₂CH₃), 3.95 (dd, 2H, CH₂), 1.73 (m, 1H, CH), 1.51 (m,4H, CH₂), 1.35 (t, 3H, —CH₂CH₃), 0.97 (t, 6H, CH₃).

LC-MS: m/z 424,426 M+H⁺

Step 35-amino-1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazole-4-carboxylicacid, 36

The title compound was prepared following the method in Example 1, Step4

¹H-NMR(CDCl₃, 300 MHz) δ 7.72 (s, 1H, ArH), 7.40 (dd, 1H, ArH), 7.32 (d,1H, ArH), 6.83 (d, 1H, ArH), 5.32 (s, 2H, ArNH₂), 5.11 (s, 2H, ArCH₂),3.95 (dd, 2H, CH₂), 1.74 (m, 1H, CH), 1.52 (m, 4H, CH₂), 1.35 (t, 3H,—CH₂CH₃), 0.97 (t, 6H, CH₃).

LC-MS: m/z 396,398 M+H⁺

The above compounds were tested for PG antagonist activity as followsusing human recombinant prostanoid receptor (DP₁, EP₁₋₄, FP, IP and TP)stable cell lines:

In order to measure the response of G_(s) and G_(i) coupled prostanoidreceptors as a Ca²⁺ signal, chimeric G protein cDNAs were used. Stablecell lines over-expressing human prostanoid DP₁, EP₁₋₄, FP, IP, and TPreceptors were established as follows:

Briefly, human prostanoid DP₁, EP₂, and EP₄ receptor cDNAs wereco-transfected with chimeric G_(qs) cDNA containing a haemagglutanin(HA) epitope; human prostanoid EP₃ receptors were co-transfected withchimeric G_(qi)-HA; human EP₁, FP, IP, and TP receptor cDNAs wereexpressed with no exogenous G-proteins. G_(qs) and G_(qi) chimeric cDNAs(Molecular Devices, Sunnyvale, Calif., U.S.A.), as well as cDNAs ofprostanoid receptors, were cloned into a pCEP₄ vector with a hygromycinB selection marker. Transfection into HEK-293 EBNA (Epstein-Barr virusnuclear antigen) cells was achieved by the FuGENE 6 transfection Reagent(Roche Applied Science, Indianapolis, Ind., USA). Stable transfectantswere selected according to hygromycin resistance. Because G_(qs) andG_(qi) contained an HA epitope, G-protein expression was detected byWestern blotting analysis using anti-mouse HA monoclonal antibody andhorseradish peroxidase (HRP)-conjugated secondary antibody, whilefunctional expression of prostanoid receptors was detected by FLIPRscreening (Matias et al., 2004). These stable cell lines were validatedusing previously published antagonists at 10 μM against serial dilutionsof standard agonists by FLIPR functional assays for Ca²⁻ Signaling (asdescribed below).

Ca²⁺ signaling studies were performed using a FLIPR TETRA system(Molecular Devices, Sunnyvale, Calif., USA) in the 384-format. This is ahigh-throughput instrument for cell-based assays to monitor Ca²⁺signaling associated with GPCRs and ion channels. Cells were seeded at adensity of 5×10⁴ cells/well in BioCoat poly-D-lysine coated, black wall,clear bottom 384-well plates (BD Biosciences, Franklin lakes, N.J., USA)and allowed to attach overnight in an incubator at 37° C. The cells werethen washed twice with HBSS-HEPES buffer (Hanks' balanced salt solutionwithout bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using an ELx405Select CW Microplate Washer (BioTek, Winooski, Vt., USA). After 60 minof dye-loading in the dark using the Ca²⁺-sensitive dye Fluo-4AM(Invitrogen, Carlsbad, Calif., USA), at a final concentration of2×10⁻⁶M, the plates were washed 4 times with HBSS-HEPES buffer to removeexcess dye and leaving 50 μl of buffer in each well. The plates werethen placed in the FLIPR TETRA instrument and allowed to equilibrate at37° C. AGN-211377 was added in a 25 μl volume to each well to give finalconcentrations of 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM; or 0.067μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.67 μM, and 1 μM for cells over-expressingTP receptors. After 4.5 minutes, a 7-point serial dilution of thestandard agonist for the corresponding receptor, in a 25 μl volume wasinjected at the final concentrations from 10⁻¹¹M to 10⁻⁵M in 10-foldserial dilution increments for cells expressing human recombinant DP₁,EP₁, EP₂, EP₃, EP₄, FP, and IP receptors. The dose range for thestandard agonist for human recombinant TP receptors was from 10⁻¹²M to10⁻⁶M. HBSS-HEPES buffer was used as the negative control for thestandard agonists. Cells were excited with LED (light emitting diode)excitation at 470-495 nm and emission was measured through an emissionfilter at 515-575 nm. Assay plates were read for 3.5 minutes using theFLIPR^(TETRA). The peak increase in fluorescence intensity was recordedfor each well. On each plate, negative controls, dose response ofpositive controls, and co-treatments of antagonist-agonist for each dosewere in triplicates. Standard agonists were as follows: DP=BW 245C,EP₁-EP₄=PGE₂, FP=17-phenyl-PGF_(2α), IP=Cicaprost, and TP=U-46619. Thepeak fluorescence change in each well containing drug was expressedrelative to vehicle controls with the standard agonist at 10⁻⁶M (thepositive control). To obtain concentration-response curves, compoundswere tested in triplicate in each plate over the desired concentrationrange.

Ca²⁺ Signal Studies on Human Recombinant Prostanoid Receptor DP₂

FLIPR functional assays were conducted at Millipore to monitor theactivity anti-asthmatic against human DP₂ receptors stably expressed inthe Chem-5 proprietary host cell line generated by Millipore. Prior tostandard agonist addition, the compounds were spotted at 10 μM alongwith vehicle control (1% Ethanol in HBSS-HEPES buffer) across the assaywells. The assay plate was incubated at room temperature for 10 minutesin the dark. Then an 8-point serial dilution dose response from 10⁻¹²Mto 10⁻⁵M of the standard agonist PGD₂ was performed. Assay plates wereread for 90 seconds using the FLIPR^(TETRA.) The fluorescencemeasurements were collected to calculate IC₅₀ values. The assays weredone at least 3 times to give n=3.

Data Processing

All plates were subjected to appropriate baseline corrections. Maximumfluorescence values were exported. The raw data of n=1 was firstprocessed by Activity Base using nonlinear regression curve fit tocalculate the percentage activity of each data point relative to thepositive control (=10⁻⁶M of the standard agonist). Then n=3 of this datawere exported to GraphPad Prism 4 to calculate the average EC₅₀ of thestandard agonist, and the IC₅₀ (the concentration of the antagonistrequired to inhibit half the standard agonist activity) were calculatedusing nonlinear regression curve fit, with constraints of bottomconstant equal to 0 and top constant equal to 100. Calculation ofKb=[Antagonist Concentration]/(IC₅₀/EC₅₀−1). When no antagonism wasdetected or when Kb≧10,000nM, the antagonist is defined as not active(NA).

The results of the above testing are reported in TABLE 1, below.

TABLE 1 Example FP DP EP1 EP2 EP3 EP4 IP TP 1 2700 400 170 NA NA 1004800 3 2 80 600 33 NA 6100 380 2400 12 3 400 1100 30 NA NA 1300 1400 304 2000 1400 140 NA NA 4800 3100 100 5 700 350 20 NA NA 860 600 18 6 NA5600 1500 8600 NA 4900 NA 500 7 NA NA 640 NA NA 3300 1800 150 8 200 140040 NA NA 1600 NA 45 9 7200 3900 440 NA NA NA NA 440 10 190 940 50 NA3900 500 1300 6 11 500 4550 30 NA NA 3300 8300 80 12 110 2500 30 NA NA600 2650 40 13 70 3500 30 NA NA 2100 7700 20 14 90 3400 30 NA NA 1300 NA20 15 140 780 45 NA NA 1500 10000 8 16 200 1600 60 NA NA 300 5100 50

As shown in TABLE 1, the preferred compounds of this invention are panantagonists having activity at the FP, DP, EP₁, EP₄ and TP receptors,but are inactive at the IP, EP₂ and EP₃ receptors. Thus, these compoundshave a biological selectivity profile making them useful in treatingdiseases and conditions which are mediated by the EP₂ and/or EP₃receptors, without the side effects mediated by the FP, DP, EP₁, EP₄ andTP receptors.

The 4-carboxylic pyrazoles included in the present invention, werecompared to 3-carboxylic acids see TABLE 2, below.

TABLE 2 Example FP DP EP1 EP2 EP3 EP4 IP TP 17 300 2300 20 NA NA NA NA30 18 1100 500 60 NA NA 5000 NA <1 19 400 2400 20 NA NA NA NA 7 20 23085 <1 NA NA 4200 NA <1 21 70 1300 10 NA 9100 NA NA 1

As shown in TABLE 2, the 3-carboxylic acid compounds are active at FP,EP1 and TP receptors but do not have significant activity at the EP4receptor. In contrast the 4-carboxylic acids of the present inventionare active at the FP, EP1, TP and EP4 receptors.

As a result, the 4-carboxylic acid compounds will exhibit morepronounced therapeutic benefit through blockade of the EP4 receptorwhilst allowing EP2, EP3 and IP these receptors to maintain theirinherent anti-inflammatory and anti-proliferative functions in responseto endogenously present prostanoids.

Thus, the compounds of this invention compound may be administered totreat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases orconditions.

For example, said condition or disease may be related to inflammation,or said DP1, FP, EP1, TP and/or EP4 receptor mediated condition ordisease may be selected from the group consisting of allergicconditions, asthma, allergic asthma, allergic rhinitis, uveitis andrelated disorders, atherosclerosis, blood coagulation disorders, bonedisorders, cancer, cellular neoplastic transformations, chronicobstructive pulmonary diseases and other forms of lung inflammation,congestive heart failure, diabetic retinopathy, diseases or conditionsrequiring a treatment of anti-coagulation, diseases requiring control ofbone formation and resorption, fertility disorders, gangrene, glaucoma,hyperpyrexia, immune and autoimmune diseases, inflammatory conditions,metastic tumor growth, migraine, mucus secretion disorders, nasalcongestion, nasal inflammation, occlusive vascular diseases, ocularhypertension, ocular hypotension, osteoporosis, rheumatoid arthritis,pain, perennial rhinitis, pulmonary congestion, pulmonary hypotension,Raynaud's disease, rejection in organ transplant and by-pass surgery,respiratory conditions, hirsutism, rhinorrhea, shock, sleep disorders,and sleep-wake cycle disorders.

Said compound may be administered as a surgical adjunct in ophthalmologyfor cataract removal and artificial lens insertion, ocular implantprocedures, photorefractive radial keratotomy and other ophthalmogicallaser procedures or as a surgical adjunct in a procedure involving skinincisions, relief of pain and inflammation and scar formation/keloidspost-surgery, for treating sports injuries and general aches and painsin muscles and joints.

Preferably, said DP₁, FP, EP₁, TP, and/or EP₄ receptor mediatedcondition or disease is an EP₁ and/or EP₄ receptor mediated condition ordisease.

Preferably, said DP₁, FP, EP₁, TP and/or EP₄ receptor mediated conditionor disease is an allergic condition, e.g. an dermatological allergy, oran ocular allergy, or a respiratory allergy, e.g. nasal congestion,rhinitis, and asthma.

Said condition or disease may be related to pain.

Said condition or disease may be selected from the group consisting ofarthritis, migraine, and headache.

Said condition or disease may be associated with the gastrointestinaltract, wherein said condition or disease may be peptic ulcer, heartburn,reflux esophagitis, erosive esophagitis, non-ulcer dyspepsia, infectionby Helicobacter pylori, alrynitis, and irritable bowel syndrome.

Said condition or disease may be selected from the group consisting ofhyperalgesia and allodynia, or said condition or disease may be relatedto mucus secretion, wherein said mucus secretion is gastrointestinal, oroccurs in the nose, sinuses, throat, or lungs.

Said condition or disease is related to abdominal cramping, e.g. saidcondition or disease may be irritable bowel syndrome.

Said condition or disease may be a bleeding disorder, or a sleepdisorder, or mastocytosis.

Said condition or disease may be associated with elevated bodytemperature, or ocular hypertension and glaucoma, or ocular hypotension.

Said condition may relate to surgical procedures to treat pain,inflammation and other unwanted sequelae wherein said surgical procedureincludes incision, laser surgery or implantation. The present inventionalso relates to a method of treating inflammation resulting frominflammatory diseases characterized by monocytic infiltration caused bythe secretion of cytokines and/or chemokines by administration, to apatient in need of said treatment, of a pharmaceutical compositioncomprising a compound of the present invention.

The current finding that the compounds of this invention are effectivein attenuating the production of TNF family cytokines (TNFα), and theclassical interleukin-1 (IL-1) family cytokines is especially important.These cytokines exert a broad spectrum of biological and pathologicaleffects. They play key roles in inflammation and RA pathogenesis bystimulating the release of multiple proinflammatory cytokines, includingthemselves, through the NFκB signaling pathway. Although alleviating thesymptoms of RA in 50-65% of patients, a TNFα antibody is very expensiveto use compared to chemically synthesized small molecules, inconvenientto administer usually requiring injections, and has been linked totuberculosis, lymphoma, and other adverse effects. Unlike a TNFαantibody that totally eliminates all circulating TNFα in the system; thecompounds of this invention only attenuate the production of TNFα byinhibiting proinflammatory PG receptors. Therefore the adverse effectsassociated with a TNFα antibody in elevating infectious and canceroustendency is less likely.

Proinflammatory elements TNF, RANTES, and MCP-1 are involved in thecascade of events in the early and late stages of atherosclerosis.Plasma MCP-1 levels have been linked to cardiovascular disease riskfactors in clinical studies. Platelet activation leads to the release ofMIP-1α, RANTES, and IL-8, which attract leukocytes and further activateother platelets. These evidences provide a direct linkage betweenhomeostasis, infection, and inflammation and the development ofatherosclerosis. The compounds of this invention are able to targetmultiple biomarkers of inflammation, thrombosis, and atherothrombosissimultaneously, which may confer pharmaceutical potential on thecompounds of this invention in treating atherosclerosis andatherothrombosis. As a result, the compounds of this invention areunlikely to be associated with cardiovascular liability as in the caseof the COXIBs, conversely it may even have a beneficial effect oncardiovascular function.

In summary, because of their ability to suppress the synthesis of somekey proinflammatory cytokines/chemokines IL-8, MCP-1, MDC, RANTES, andTNFα, the compounds of the present invention are not only at least aseffective as COXIBs and NSAIDs in RA treatment, but also are a safertherapy in RA treatment. They are also a potential therapy forcardiovascular diseases.

The compounds of this invention treat or prevent inflammation at leastin part by the decreasing the amount of the secretion of certaincytokines and/or chemokines that result from the exposure of the patientto a stimulant.

In particular, the secretion of VEGF, MIP-1β, IL-8, MCP-1, MDC, andRANTES is reduced in those instances where said secretions are triggeredby lipopolysaccharides (LPS) and or TNFα.

Interleukin-8 (IL-8): functions as a potent chemo attractants andactivator of neutrophils, IL-8 is produced in response to stimulationwith either IL-1 or TNFα. IL-8 not only accounts for a significantproportion of the chemotactic activity for neutrophils in rheumatoidarthritis (RA) synovial fluids, but also is a potent angiogenic factorin the RA synovium.

Monocyte chemo attractant protein-1 (MCP-1, or CCL-2): is not onlybelieved to play a role in inflammatory diseases characterized bymonocytic infiltration, such as RA rheumatoid arthritus, psoriasis, andatherosclerosis, but is also implicated in other diseases, such asatopic dermatitis, renal disease, pleurisy, allergy and asthma, colitis,endometriosis, polymyositis and dermatomyositis, uveitis, restenosis,brain inflammation and obesity. MCP-1 also controls leukocytetrafficking in vascular cells involved in diabetes and diabetes-inducedatherosclerosis. MCP-1 antibodies are potential therapeutic agents fortreating MCP-1/CCR2-mediated multiple inflammatory diseases.

Tumor necrosis factor α (TNFα): mainly secreted by macrophages andrecognized for its importance in activating the cytokine cascade. TNFαstimulates the production of proinflammatory cytokines/chemokines,collagenases, metalloproteinases, and other inflammatory mediators;activates endothelial cells and neutrophils; promotes T- and B-cellgrowth, as well as stimulating bone resorption. The TNFα antibodyinfliximab not only decreases the production of local and systemicproinflammatory cytokines/chemokines, but also reduces serum MMP-3production, nitric oxide synthase activity, VEGF release, andangiogenesis in inflamed joints.

Macrophage-derived chemokine (MDC) induces chemotaxis formonocyte-derived dendritic cells, activated T cells and natural killer(NK) cells (Ho et al., 2003). Highly expressed by the three major celltypes involved in allergic inflammation: eosinophils, basophils, and Th2lymphocytes (Garcia et al., 2005), as well as highly expressed in atopicdermatitis (Pivarcsi et al., 2005), MDC plays a role in inflammatorydiseases such as allergic asthma and atopic dermatitis (Ho et al.,2003). Significantly enhanced in keratinocytes of patients with atopicdermatitis, MDC could be a candidate therapeutic target for inflammatoryskin disease such as atopic dermatitis (Qi et al., 2009). MDC is alsoimplicated in disease activity of RA. After combination treatment withthe disease-modifying anti-rheumatic drugs leflunomide and methotrexatein RA patients, plasma MCP-1 and MDC concentrations were significantlylower, and so was the recruitment of inflammatory cells into the sitesof inflammation (Ho et al., 2003). Moreover, MDC also amplify plateletactivation and has been associated with the pathogenesis ofatherosclerotic disease including thrombosis (Gleissner et al., 2008).

Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)is a chemo attractant for blood monocytes, memory T-helper cells andeosinophils, and plays an active role in recruiting leukocytes intoinflammatory sites. It also stimulates the release of histamine frombasophils, activates eosinophils and causes hypodense eosinophils, whichis associated with diseases such as asthma and allergic rhinitis. RANTESreceptor CCR5 is also expressed on cells involved in atherosclerosis(e.g. monocytes/macrophages, T lymphocytes, or Th1-type cells), and isspecialized in mediating RANTES-triggered atherosclerotic plaqueformation (Zernecke et al., 2008). Like MCP-1, stimulation with RANTESenhances production of IL-6 and IL-8 in RA fibroblast-like synovialcells; elevated MMP-3 production by chondrocytes, and inhibitedproteoglycan synthesis and enhanced proteoglycan release from thechondrocytes (Iwamoto et al., 2008). Both MCP-1 and RANTES were found toplay an important role in allergic lung inflammation, lung leukocyteinfiltration, bronchial hyper-responsiveness, and the recruitment ofeosinophils in the pathogenesis of asthma (Conti et al., 2001). Similarto MCP-1, RANTES also enhances the inflammatory response within thenervous system, which plays an apparent role in the pathogenesis ofmultiple sclerosis (Conti et al., 2001). Inhibitors for RANTES mayprovide clinical benefits in treating inflammation, CNS disorders,parasitic disease, cancer, autoimmune and heart diseases (Castellani etal., 2007).

While the use of the compounds of this invention are shown to decreasethe secretion of the above cytokines in FIGS. 2 through 9, it isbelieved that the compounds of this invention are effective to decreasethe secretion of ENA-7, PAI-1, CD-10, G-CSF, GM-CSF, IL-1{acute over(α)} and IL-18, as well.

The compounds of this invention may be also tested for efficacy intreating uveitis as described below.

Arachidonate Induced Uveitis

The rational for this protocol is to use arachidonate to directlyproduce ocular anterior segment uveitis, as opposed to usinglipopolysaccharide (LPS) to indirectly release arachidonic acid.

Induction of Uveitis:

Conscious male or female Dutch-belted pigmented rabbits weighing 2.5-3kg were used for all in vivo slit lamp studies. Four animals wereemployed per test group. The right eye of each animal receiving 35 μl oftopically administered test and the contralateral left eye of eachanimal receiving 35 μl of topically administered vehicle (t=0 minutes),followed 30 minutes later by treatment with 35 μl of 0.5% sodiumarachidonate onto the surface of both eyes (t=30 minutes). Both eyeswere examined by slit lamp 60 minutes following sodium arachdionatechallenge (t=90 minutes) at 16× magnification under both white light andblue light illumination at an approximate angle of 45° through 1 mm and5 mm slit widths.

Measurement of Anterior Chamber Leukocyte Infiltration:

Anterior chamber leukocyte infiltration was measured using a numericalscoring system to estimate cell number per field defined by a 5 mm slitwidth: 0=no cells per field (no response); 1=1−10 cells per field(mild); 2=11−20 cells per field (moderate); 3=26−50 cells per field(severe); 4=>50 cells per filed (florid). Results are reported as themean score value±S.E.M.

The compounds of this invention were tested according to the methoddescribed in “Characterization of Receptor Subtypes Involved inProstanoid-Induced Conjunctival Pruritis and Their Role in MediatingConjunctival Itching”, Vol. 279, No.1,(JPET)279, 137-142′ 1996 for theirefficacy in alleviating itch. The results are reported in FIGS. 10 and11. The results in both experiments showed a significantly lower numberof itch-scratch episodes with the use of the compounds of FIGS. 3 and 3(a) thereby indicating that the compounds of this invention are useful intreating allergic conjunctivitis.

The compounds of FIGS. 3 and 3( a) were tested for mutagenicity by meansof the Ames Test using Strains TA 98 and TA 100. The results werenegative for both compounds.

Finally, said condition that may be treated with the compounds of thisinvention may be related to pain and inflammation and post-surgical scarand keloid formation.

In view of the various diseases and conditions that may be treated withthe compositions of this invention there is provided a pharmaceuticalproduct comprising a compound having the following formula:

Wherein X is O, NR₇ or (CH₂)_(n), wherein n is 0 or an integer of 1 or2;

Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3;

Z is selected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3;

W is hydrocarbyl or substituted hydrocarbyl;

R₁ is selected from the group consisting of OR₇, N(R₇)₂, and N(R₇)SO₂R₇;

R₂ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₄ is selected from the group consisting of H, NH₂, alkyl,nitrogen-substituted alkyl and halogen-substituted alkyl;

R₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R₆ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy; and,

R₇ is selected from the group consisting of H, hydrocarbyl andsubstituted hydrocarbyl, e.g. carbocyclic aryl and alkyl or apharmaceutically acceptable salt or a prodrug thereof, wherein saidproduct is packaged and labeled for the treatment or prevention of adisease or condition selected from the group consisting of uveitis,allergic conditions, asthma, allergic asthma, allergic rhinitis,atherosclerosis, blood coagulation disorders, bone disorders, cancer,cellular neoplastic transformations, chronic obstructive pulmonarydiseases and other forms of lung inflammation, congestive heart failure,diabetic retinopathy, diseases or conditions requiring a treatment ofanti-coagulation, diseases requiring control of bone formation andresorption, fertility disorders, hyperpyrexia, gangrene, glaucoma,hypothermia, immune and autoimmune diseases, inflammatory conditions,metastic tumor growth, migraine, mucus secretion disorders, nasalcongestion, nasal inflammation, occlusive vascular diseases, ocularhypertension, ocular hypotension, osteoporosis, pain, perennialrhinitis, pulmonary congestion, pulmonary hypotension, Raynaud'sdisease, rejection in organ transplant and by-pass surgery, respiratoryconditions, rheumatoid arthritis, rhinorrhea, shock, sleep disorders,sleep-wake cycle disorders, sports injuries, muscle aches and pains, andsurgical adjunct for minimizing pain, inflammation and scar/keloidformation.

Those skilled in the art will readily understand that for administrationthe compounds disclosed herein can be admixed with pharmaceuticallyacceptable excipients which, per se, are well known in the art.Specifically, a drug to be administered systemically, it may beformulated as a powder, pill, tablet or the like, or as a solution,emulsion, suspension, aerosol, syrup or elixir suitable for oral orparenteral administration or inhalation.

For solid dosage forms, non-toxic solid carriers include, but are notlimited to, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum,cellulose, glucose, sucrose and magnesium carbonate. The solid dosageforms may be uncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distcarate maybe employed. They may also be coated by the technique described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, which areincorporated by reference in their entireties, to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the compounds of the present invention andoptional pharmaceutical adjutants in a carrier, such as for example,water, saline, aqueous dextrose, glycerol, ethanol and the like, tothereby form a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectableformulations can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol, ethanoland the like. In addition, if desired, the injectable pharmaceuticalcompositions to be administered may also contain minor amounts ofnon-toxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like.

The amount of the presently useful compound or compounds of the presentinvention administered is, of course, dependent on the therapeuticeffect or effects desired, on the specific mammal being treated, on theseverity and nature of the mammal's condition, on the manner ofadministration, on the potency and pharmacodynamics of the particularcompound or compounds employed, and on the judgment of the prescribingphysician. The therapeutically effective dosage of the presently usefulcompound or compounds is preferably in the range of about 0.5 ng/kg/dayor about 1 ng/kg/day to about 100 mg/kg/day.

For ophthalmic application, solutions are often prepared using aphysiological saline solution as a major vehicle. Ophthalmic solutionsshould preferably be maintained at a comfortable pH with an appropriatebuffer system. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

Similarly, an ophthalmically acceptable antioxidant for use in thepresent invention includes, but is not limited to, sodium metabisulfite,sodium thiosulfate, acetylcysteine, butylated hydroxyanisole andbutylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edentatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound of the present invention are employed.Topical formulations may generally be comprised of a pharmaceuticalcarrier, cosolvent, emulsifier, penetration enhancer, preservativesystem, and emollient.

The actual dose of the compounds of the present invention depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan.

The present invention is not to be limited in scope by the exemplifiedembodiments, which are only intended as illustrations of specificaspects of the invention. Various modifications of the invention, inaddition to those disclosed herein, will be apparent to those skilled inthe art by a careful reading of the specification, including the claims,as originally filed. It is intended that all such modifications willfall within the scope of the appended claims.

What is claimed is:
 1. A compound, that is a 1-[(5-halo or alkyl orfluoroalkyl or alkoxy-2-{(hydrocarbyl or substitutedhydrocarbyl)oxy}phenyl)methyl]-(3 or 5 alkyl orfluoroalkyl)-1H-pyrazole-4-(carboxylic acid or methylene carboxylicacid) or an alkyl or aryl ester or sulfonamide thereof.
 2. The compoundof claim 1 wherein said halo is selected from the group consisting ofchloro and bromo.
 3. The compound of claim 1 wherein said hydrocarbyl isselected from the group consisting of alkyl and carbocyclic aryl.
 4. Thecompound of claim 3 wherein said hydrocarbyl is selected from the groupconsisting of branched chain alkyl and phenyl.
 5. The compound of claim4 wherein said hydrocarbyl is selected from the group consisting ofbranched chain alkyl having from 4 to 7 carbons.
 6. The compound ofclaim 1 wherein said compound is a 1-[(5-Chloro or bromo-ortrifluoromethyl-2-{hydrocarbyloxy}phenyl)methyl]-(3 or 5 methyl)-1H-pyrazole-4-carboxylic acid.
 7. The compound of claim 6 wherein saidhydrocarbyl is selected from the group consisting of alkyl andcarbocyclic aryl.
 8. The compound of claim 6 wherein said hydrocarbyl isselected from the group consisting of branched chain alkyl and phenyl.9. The compound of claim 6 wherein said hydrocarbyl a branched chainalkyl having from 4 to 7 carbons.
 10. The compound of claim 1 that isselected from the group consisting of:1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-methylenecarboxylicacid;1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;1-[(5-Bromo-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid;1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-1H-pyrazole-4-carboxylicacid;1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxylicacid;1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-3-propyl-1H-pyrazole-4-carboxylicacid;1-[(5-chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-propyl-1H-pyrazole-4-carboxylicacid;1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid;1-[(5-trifluoromethyl-2-{2-ethylbutyloxy}phenyl)methyl]-3-methyl-1H-pyrazole-4-carboxylicacid;1-[(5-Chloro-2-{2-ethylbutyloxy}phenyl)methyl]-5-methyl-1H-pyrazole-4-carboxylicacid; 1-[5-chloro-2-isobutoxy-benzyl)-5-methyl-1h-pyrazole-4-carboxylicacid;1-(5-chloro-2-cyclopentylmethoxy-benzyl)-5-methyl-1h-pyrazole-4-carboxylicacid; 1-(5-bromo-2-isobutoxy-benzyl)-5-methyl-1h-pyrazole-4-carboxylicacid;1-[5-bromo-2-(2,2-dimethyl-propoxy)-benzyl]-5-methyl-1h-pyrazole-4-carboxylicacid;1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-5-methyl-1h-pyrazole-4-carboxylicacid; and,5-amino-1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazole-4-carboxylicacid.
 11. A compound having the following formula:

Wherein: X is O, NR₅ or (CH₂)_(n), wherein n is 0 or an integer of 1 or2; Y is (CH₂)_(m), wherein m is 0 or an integer of from 1 to 3; Z isselected from the group consisting of O, S, SO, SO₂ and (CH₂)_(p),wherein p is 0 or an integer of from 1 to 3; W is hydrocarbyl orsubstituted hydrocarbyl; R₁ is selected from the group consisting ofOR₇, N(R₇)₂, and N(R₇)SO₂R₇; R₂ is selected from the group consisting ofH, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyanoand hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl,alkoxy or aryloxy; R₄ is selected from the group consisting of H, NH₂,alkyl, nitrogen-substituted alkyl and halogen-substituted alkyl; R₅ isselected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy,aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, aminoand cyano-substituted alkyl, aryl, alkoxy or aryloxy; R₆ is selectedfrom the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy,halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino andcyano-substituted alkyl, aryl, alkoxy or aryloxy; and, R₇ is selectedfrom the group consisting of H, hydrocarbyl and substituted hydrocarbyl.12. The compound of claim 11, wherein R₁ is OH.
 13. The compound ofclaim 11, wherein R₂ is selected from the group consisting of H, alkyland halogen-substituted alkyl.
 14. The compound of claim 11, wherein R₄is selected from the group consisting of H, alkyl andhalogen-substituted alkyl.
 15. The compound of claim 11, wherein R₁ is Xis (CH₂)_(n), wherein n is 0 or
 1. 16. The compound of claim 11, whereinR₅ is selected from the group consisting of H, hydroxy, alkyl, aryl,alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy. 17.The compound of claim 11, wherein R₅ is chloro or bromo.
 18. Thecompound of claim 11, wherein R₆ is selected from the group consistingof H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino,cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl,aryl, alkoxy or aryloxy.
 19. The compound of claim 18, wherein R₆ is H.20. The compound of claim 11, wherein Y is absent.
 21. The compound ofclaim 11, wherein Z is O.
 22. The compound of claim 11, wherein W isselected from the group consisting of alkyl, aryl, alkoxy, aryloxy andhydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxyor aryloxy.